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Experimental and clinical pharmacology
New oral anticoagulant drugs mechanisms
of action
Timothy Brighton, Haematologist, South Eastern Area Laboratory Service and Prince of Wales
Hospital, Sydney
Summary
In 2008, two new oral anticoagulant drugs were
registered in Australia for the prevention of
venous thrombosis after elective knee or hip
replacement. Rivaroxaban is a direct reversible
competitive antagonist of activated factor X.
Dabigatran etexilate is a direct reversible
competitive antagonist of thrombin. Both drugs
are effective anticoagulants which offer potential
advantages over heparin and warfarin.
Key words: dabigatran etexilate, rivaroxaban.
(Aust Prescr 2010;33:3841)
Introduction
Since the 1960s warfarin has been the only oral anticoagulant
drug in regular use for treating patients with thromboembolic
disease. In November 2008 the Therapeutic Goods Administration
approved two new oral anticoagulant drugs rivaroxaban and
dabigatran etexilate for the prevention of venous thrombosis in
patients having elective knee or hip replacement.
Mechanisms of action
Rivaroxaban and dabigatran etexilate have low molecular
weights. They have specic and restricted anticoagulant
activities (Fig. 1). Although their mechanisms of action are
different, the specicity of activity has no known clinical
relevance and both drugs are effective anticoagulants.
Rivaroxaban is a competitive reversible antagonist of
activated factor X (Xa). Factor Xa is the active component of
the prothrombinase complex that catalyses conversion of
prothrombin (factor II) to thrombin (factor IIa).
Dabigatran etexilate is a competitive reversible non-peptide
antagonist of thrombin. Thrombin is a multifunctional enzyme
which converts brinogen to brin, cross-linking brin
monomers via activation of factor XIII and augmenting further
thrombin production via the activation of factors V and VIII.
It also activates platelets, generates anticoagulant activity via
activation of protein C and initiates numerous cellular processes
including wound healing. Most of the actions of thrombin are
inhibited in vitro by dabigatran etexilate.
Pharmacokinetics
The essential properties of the new anticoagulants are
compared to warfarin in Table 1. Their main advantages
are a rapid onset of anticoagulant effect, more predictable
pharmacokinetics, and a lower potential for clinically important
interactions with food, lifestyle and other drugs. There is no
requirement for routine monitoring and dose adjustment as
required with warfarin.
Rivaroxaban
Rivaroxaban
1
10 mg tablets are well absorbed (80%
bioavailability) with no effect of food on absorption or
pharmacokinetic parameters. Plasma concentrations peak at
2.54 hours. The plasma elimination half-life is 59 hours in
young adults and 1113 hours in older people due to the age-
related decline in renal function. This permits once- or twice-
daily dosing.
Rivaroxaban is metabolised by liver enzymes, principally
cytochrome P450 3A4, and also by cytochrome-independent
mechanisms. There are no known active metabolites.
Rivaroxaban has a dual mechanism of excretion. Approximately
66% of the dose is excreted via the kidneys, in roughly equal
proportions of rivaroxaban and inactive metabolites. The
remainder is excreted by the faecal-biliary route. Intestinal
excretion of rivaroxaban appears to be mediated, at least in
part, by P-glycoprotein, a transport protein, because potent
P-glycoprotein inhibitors will increase plasma concentrations
of rivaroxaban.
Dabigatran
Dabigatran is a hydrophilic polarised membrane-impermeable
molecule which is not absorbed after oral dosing. The oral
formulation, dabigatran etexilate,
2
is a prodrug with low
bioavailability (approximately 6.5%) and its absorption in
the stomach and small intestine is dependent on an acid
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environment. To promote this microenvironment, dabigatran
etexilate is formulated in tartaric acid-containing capsules.
Esterases found in enterocytes, plasma and the liver rapidly
convert dabigatran etexilate to dabigatran. The drug enters
the portal vein as a combination of prodrug and active
compound, but once in the liver bioconversion of the
prodrug is completed. Plasma concentrations of dabigatran
peak 0.52 hours after an oral dose.
The plasma elimination half-life is 79 hours, and 1214 hours
in older people. This permits once- or twice-daily dosing.
About 20% of dabigatran is conjugated and excreted via the
biliary system. The cytochrome P450 system plays no part
in the metabolism of dabigatran and there are no active
metabolites. The remaining 80% of circulating dabigatran
is excreted unchanged via the kidneys. The medication is
presented in two formulations, 75 mg and 110 mg capsules.
Interactions
Diseases and drug interactions may alter the anticoagulant
effect of these drugs. This can reduce efcacy or increase the
risk of bleeding.
Rivaroxaban
Disease- or drug-induced reductions in faecal and
renal clearance can increase the anticoagulant effect of
rivaroxaban. It is currently contraindicated in patients with
severe liver disease because metabolic inactivation may
be impaired, and in patients with severe renal impairment
(creatinine clearance under 30 mL/min).
To date, clinical trials have found no signicant
pharmacokinetic interactions with aspirin, non-steroidal
anti-inammatory drugs, antacids, histamine H
2
-receptor
antagonists or digoxin. Caution is needed in patients
receiving treatment with potent inhibitors of both CYP3A4
and P-glycoprotein, such as ketoconazole, macrolide
antibiotics (for example clarithromycin) or protease inhibitors
(for example ritonavir, atazanavir). These drugs increase the
anticoagulant effect.
Dabigatran
Reduced renal clearance increases the total exposure
(area under the concentration-time curve AUC) and
the elimination half-life of dabigatran. This can cause an
exaggerated anticoagulant effect. In elderly patients with
Fig. 1
Site of action of new anticoagulant drugs
Prothrombin
Dabigatran
etexilate
Fibrinogen Fibrin
Intrinsic activation Extrinsic activation
Factor XII
Factor XI
Factor VIII
Factor VII
Factor IXa Factor X
Factor Xa
Thrombin
Rivaroxaban
Surface contact Vessel injury
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calculated moderate (creatinine clearance 3050 mL/min)
or severe (creatinine clearance 1030 mL/min) renal
insufciency, the AUC was increased 2.7 and 6-fold
respectively, while the plasma elimination half-life increased
at least twofold. Dabigatran should not be used in patients
with severe renal impairment (creatinine clearance under
30 mL/min). It does not undergo hepatic metabolism and
no change in total dabigatran exposure was seen in
12 patients with moderate hepatic insufciency (Child-Pugh
B classication).
The absorption of dabigatran etexilate is reduced by 2025%
if patients are also given proton pump inhibitors.
Table 1
Comparison of oral anticoagulants
Property Warfarin Rivaroxaban Dabigatran etexilate
Anticoagulant action Reduced synthesis of
functional clotting factors II,
VII, IX and X
Direct competitive reversible
inhibition of activated factor X
Direct competitive
reversible inhibition of
thrombin
Prodrug No No Yes
Bioavailability Almost 100% 80% 6.5%
Onset of anticoagulant action 3672 hours Within 30 minutes
T
max
2.54 hours
Within 30 minutes
T
max
0.52 hours
Duration of anticoagulant
action
4896 hours 24 hours 2436 hours
Elimination half-life
(anticoagulant activity)
2060 hours 59 hours in young adults
1113 hours in older adults
79 hours in young adults
1214 hours in older adults
Predictable pharmacokinetics No Yes Yes
Interactions with diet or
alcohol
Yes, clinically signicant Low potential Low potential
Drug interactions Numerous clinically
signicant interactions
Potent cytochrome P450 3A4
and P-glycoprotein inhibitors
augment anticoagulant
effect (e.g. ketoconazole,
clarithromycin, ritonavir)
Proton pump inhibitors
reduce absorption
Possible interactions with
P-glycoprotein inhibitors
and inducers
Dosing and dose adjustments Dose individualised for each
patient, requires frequent INR
monitoring and adjustment
Fixed according to clinical
indication
Fixed according to clinical
indication
Monitoring INR every 12 weeks No routine monitoring
required
No routine monitoring
required
Use in liver failure Contraindicated or caution
advised
Contraindicated as hepatic
metabolism
Possibly safe as no hepatic
metabolism but caution
advised
Use in severe renal
impairment
No dose adjustment required Increased drug exposure and
elimination half-life in renal
impairment
Safety and dosing not yet
established
Contraindicated in severe
renal impairment
Increased drug exposure
and elimination half-life in
renal impairment
Safety and dosing not yet
established
Contraindicated in severe
renal impairment
Use in pregnancy Category D
Teratogenic in rst trimester
Contraindicated as safety not
established (excluded from
clinical trials)
Contraindicated as safety
not established (excluded
from clinical trials)
Reversibility after cessation Several days, requires
synthesis of clotting factors
24 hours, dependent on
plasma concentration and
elimination half-life
2436 hours, dependent on
plasma concentration and
elimination half-life
Antidote Immediate reversal with
plasma or factor concentrate
Reversal within hours with
vitamin K
None available None available
INR international normalised ratio
T
max
time to maximum concentration
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Co-administration of dabigatran etexilate with food delays
the peak plasma concentration by two hours and increases
the AUC of dabigatran by 27%. In postoperative patients, the
peak plasma concentrations are not achieved for 79 hours
if dabigatran is given on the day of surgery. These two
observations do not seem clinically important.
Clinical studies have not found pharmacokinetic interactions
with atorvastatin or diclofenac, consistent with the
observation that the cytochrome P450 system plays no role
in the metabolism of dabigatran. Interactions have been
found with P-glycoprotein inhibitors (quinidine, amiodarone)
with increased total dabigatran exposure (AUC increased
up to twofold). P-glycoprotein inducers may reduce
systemic exposure of dabigatran. No changes in digoxin (a
P-glycoprotein substrate) or dabigatran concentrations were
noted when the drugs were co-administered.
Safety
Rivaroxaban and dabigatran etexilate have not been shown
to be safe and effective in important groups of patients who
may require anticoagulant therapy. These groups include
patients with severe renal or hepatic impairment (dabigatran
does not undergo hepatic metabolism and may be safe in
patients with hepatic disease), children, and pregnant or
lactating women.
The major adverse effect of all anticoagulant medications
is bleeding. There is no published evidence yet that the
new anticoagulant medications cause less bleeding than
heparin or warfarin. Fatal and major bleeding will be further
increased with concomitant anticoagulant and antiplatelet
therapies. Antiplatelet medications should be avoided while
on new anticoagulant medications, unless the benets
of combined therapy outweigh the risks. No antidotes to
reverse rivaroxaban or dabigatran anticoagulant effects are
available. The anticoagulant effect will not be reversed by
administration of vitamin K or plasma infusion.
Compared to enoxaparin, there is no signicant increase in
abnormal liver function tests with either drug. The possibility
of hepatotoxicity with rivaroxaban cannot be excluded until
data are available from longer-term usage (up to 24 months)
in venous thrombosis treatment, and stroke prevention
studies.
3

Conclusion
Rivaroxaban and dabigatran etexilate are two oral
anticoagulant medications recently registered in Australia
for prevention of venous thrombosis after lower limb
arthroplasty. Both drugs have specic but different
mechanisms of action, a rapid onset of anticoagulant activity,
less variable pharmacokinetics than warfarin, and a low
potential for interactions with diet and other drugs. They are
given in xed doses and do not require routine monitoring.
The safety and efcacy of these drugs in the prevention
of venous thrombosis in patients other than those having
arthroplasty remains to be established in clinical trials.
References
1. Verma AK, Brighton TA. The direct factor Xa inhibitor
rivaroxaban. Med J Aust 2009;190:379-83.
2. Stangier J, Rathgen K, Stahle H, Gansser D, Roth W. The
pharmacokinetics, pharmacodynamics and tolerability of
dabigatran etexilate, a new oral direct thrombin inhibitor, in
healthy male subjects. Br J Clin Pharmacol 2007;64:292-303.
3. U.S. Food and Drug Administration. Minutes of Xarelto
(rivaroxaban) cardiovascular and renal drugs Advisory
Committee meeting. 2009 Mar 19.
www.fda.gov/downloads/AdvisoryCommittees/Committees
MeetingMaterials/Drugs/CardiovascularandRenalDrugs
AdvisoryCommittee/UCM143660.pdf [cited 2010 Mar 12]
Dr Brighton has received an honorarium from Bayer for an
advisory role on steering committees for the EINSTEIN phase II
and III clinical studies (rivaroxaban). He has received honoraria
from Boehringer Ingelheim for an Australian advisory
committee role and lectures.
Self-test questions
The following statements are either true or false
(answers on page 59)
1. The doses of rivaroxaban and dabigatran etexilate are
adjusted according to the patient's INR.
2. The anticoagulant effects of rivaroxaban and
dabigatran etexilate are reversed by vitamin K.
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